Activation and participation of cardiac progenitor cells (CPCs) in regeneration are critical for effective repair in the wake of pathologic injury. We have found that CPC activation and lineage commitment involve increased energy demand and activation of mitochondrial biogenesis. Although the primary function of mitochondria is to provide the cell with ATP through oxidative phosphorylation, mitochondria can quickly become death- promoting organelles. Not surprisingly, cells have developed a defense mechanism against aberrant mitochondria that can harm the cell. The E3 ubiquitin ligase Parkin marks dysfunctional mitochondria for degradation by the autophagosome-lysosomal pathway. Unfortunately, aging is associated with reduced autophagy, which leads to inadequate removal of dysfunctional mitochondria. The regulation of mitochondrial autophagy in CPCs and the correlation between mitochondrial function and CPC aging are essentially unknown. In this proposal, we will explore the hypothesis that mitochondrial quality control in CPCs is reduced with age, which leads to accumulation of defective mitochondria and impaired function. This hypothesis will be tested with two aims.
In Aim 1, we will determine the effect of mitochondrial DNA (mtDNA) mutations and aging on CPC function. Using a mouse model carrying a proofreading defective mtDNA polymerase gamma (POLGm/m), we will investigate the effect of accumulating mtDNA mutations on mitochondrial function, as well as survival, proliferation, and differentiation of CPCs. We will also compare viability and function of WT and POLGm/m CPCs in vitro and in vivo, and evaluate the extent and efficiency of repair and improvement in cardiac function after injury.
In Aim 2, we will investigate the functional role of Parkin-mediated mitophagy in WT and POLGm/m CPCs at different ages. We will also explore the functional consequences of Parkin-deficiency in CPCs in vitro and in vivo. These studies will provide novel insights into the importance of mitochondrial clearance via autophagy in CPCs. We will also gain important new understanding of basic CPC function and survival, which can ultimately be used to enhance their regenerative capacity in the injured heart.
Cardiac progenitor cells (CPCs) are currently being used in clinical trials and show promising results in improving cardiac function in patients with heart disease. Unfortunately, the function of these cells is reduced with age, and it is unclear why this occurs. This proposal will provide important new understanding of basic CPC function and survival which can ultimately be used to enhance their regenerative capacity in patients with heart disease.
| Orogo, Amabel M; Gustafsson, Åsa B (2015) Therapeutic targeting of autophagy: potential and concerns in treating cardiovascular disease. Circ Res 116:489-503 |
| Orogo, Amabel M; Gonzalez, Eileen R; Kubli, Dieter A et al. (2015) Accumulation of Mitochondrial DNA Mutations Disrupts Cardiac Progenitor Cell Function and Reduces Survival. J Biol Chem 290:22061-75 |
